Alessandra Fusco

Traumatic brain injury and subarachnoid haemorrhage are conditions at high risk for hypopituitarism: screening study at 3 months after the brain injury

objective  Acquired hypopituitarism in adults is obviously suspected in patients with primary hypothalamic–pituitary diseases, particularly after neurosurgery and/or radiotherapy. That brain injuries (BI) can cause hypopituitarism is commonly stated and has been recently emphasized but the management of BI patients does not routinely include neuroendocrine evaluations.

Occurrence of Pituitary Dysfunction following Traumatic Brain Injury

Traumatic brain injury (TBI) may be associated with impairment of pituitary hormone secretion, which may contribute to long-term physical, cognitive, and psychological disability. We studied the occurrence and risk factors of pituitary dysfunction, including growth hormone deficiency (GHD) in 50 patients (mean age 37.6 +/- 2.4 years; 40 males, age 20-60 years; 10 females, age 23-87 years) with TBI over 5 years. Cranial or facial fractures were documented in 12 patients, and neurosurgery was performed in 14. According to the Glasgow Coma Scale (GCS), 16 patients had suffered from mild, 7 moderate, and 27 severe TBI. Glasgow Outcome Scale (GOS) indicated severe disability in 5, moderate disability in 11, and good recovery in 34 cases. Basal pituitary hormone evaluation, performed once at times variable from 12 to 64 months after TBI, showed hypogonadotrophic hypogonadism in 7 (14%), central hypothyroidism in 5 (10%), low prolactin (PRL) levels in 4 (8%), and high PRL levels in 4 (8%) cases. All subjects had normal corticotrophic and posterior pituitary function. Seven patients showed low insulin-like growth factor-I (IGF-I) levels for age and sex. Results of GHRH plus arginine testing indicated partial GHD in 10 (20%) and severe GHD in 4 (8%) cases. Patients with GHD were older (p <0.05) than patients with normal GH secretion. Magnetic resonance imaging demonstrated pituitary abnormalities in 2 patients; altogether pituitary dysfunction was observed in 27 (54%) patients. Six patients (12%) showed a combination of multiple abnormalities. Occurrence of pituitary dysfunction was 37.5%, 57.1%, and 59.3% in the patients with mild, moderate, and severe TBI, respectively. GCS scores were significantly (p <0.02) lower in patients with pituitary dysfunction compared to those with normal pituitary function (8.3 +/- 0.5 vs. 10.2 +/- 0.6). No relationship was detected between pituitary dysfunction and years since TBI, type of injury, and outcome from TBI. In conclusion, subjects with a history of TBI frequently develop pituitary dysfunction, especially GHD. Therefore, evaluation of pituitary hormone secretion, including GH, should be included in the long-term follow-up of all TBI patients so that adequate hormone replacement therapy may be administered.

Increased prevalence of radiological spinal deformities in adult patients with GH deficiency: influence of GH replacement therapy.

This cross‐sectional study shows that a high number of untreated adult patients with GHD develop radiological vertebral deformities. Patients undergoing GH replacement treatment showed a significantly lower prevalence of vertebral deformities versus treated patients in the presence of similar BMD, as assessed by DXA.

Prevalence of Vertebral Fractures in Men with Acromegaly

CONTEXT Data on osteoporotic fractures in acromegaly are limited. An increased prevalence of radiological vertebral fractures was already observed in postmenopausal women with active acromegaly. It is unknown whether this observation may reflect a more general increased risk of fractures in acromegaly. DESIGN This was a cross-sectional study. SETTING The study was conducted at referral centers. PATIENTS AND CONTROL SUBJECTS Subjects included 40 males with acromegaly (25 patients with controlled disease and 15 patients with active disease) and 31 control males, with age and gonadal status comparable with the patients. INTERVENTIONS Evaluation of vertebral fractures (quantitative morphometric analysis) and bone mineral density (BMD) at lumbar spine and total hip (dual energy X-ray absorptiometry) was done. MAIN OUTCOME MEASURE Vertebral fractures were assessed. RESULTS Although BMD was not significantly different between acromegalic patients and control subjects, the prevalence of vertebral fractures was higher in acromegalic patients as compared with the control subjects (57.5 vs. 22.6%; chi(2): 8.7; P = 0.003). Fractured and nonfractured acromegalic patients showed no significant difference in age and BMD Z-score. However, acromegalic patients with fractures had serum IGF-I values significantly higher and duration of active disease significantly longer with respect to patients without fractures. Moreover, patients with fractures showed significantly longer untreated hypogonadism as compared with patients without fractures. In a multivariate logistic regression analysis, the duration of active acromegaly was the only risk factor significantly correlated with the occurrence of fractures (odds ratio 1.1, confidence interval 1.04-1.6). CONCLUSIONS This study reports for the first time a high prevalence of osteoporotic vertebral fractures in an unselected acromegalic male population generally considered at low risk of osteoporosis, suggesting that complicated osteoporosis is an important comorbidity of acromegaly.

Prognostic significance of the Ki-67 labeling index in growth hormone-secreting pituitary adenomas.

CONTEXT Ki-67 is a marker of proliferation activity associated with invasiveness and prognosis in human tumors. OBJECTIVE The aim of the study was to evaluate the Ki-67 index prognostic relevance in a group of acromegalic patients who underwent transsphenoidal surgery for a GH-secreting pituitary adenoma. MATERIAL AND METHODS We selected 68 consecutive acromegalic patients referred to our hospital during a 5-yr period. The Ki-67 index was determined by immunohistochemistry on tissue samples obtained from each adenoma after surgery. Those patients who were not completely cured after surgery began medical therapy with somatostatin analogs (SSAs). Periodical pituitary magnetic resonance imaging and hormonal evaluation were performed during the follow-up. RESULTS Twenty-eight of 68 patients were cured after surgery (41%). Among the 40 patients treated with SSAs, 13 were considered uncontrolled. Pituitary magnetic resonance imaging showed residual/recurrent disease in 25 of 68 patients after 6 months. No correlation was found between Ki-67 index and age, tumor size, GH, or IGF-I plasma levels. Tumors described as having cavernous sinus invasion had a higher mean Ki-67 index as compared with noninvasive tumors (P < 0.01). The Ki-67 index was significantly lower in tumors in patients cured after surgery as compared with patients considered not cured (P < 0.01) and in tumors in patients controlled by SSA therapy as compared with patients considered as uncontrolled (P < 0.05). CONCLUSION The Ki-67 labeling index may predict clinical outcome in postsurgical management of acromegalic patients. We suggest routine Ki-67 evaluation in GH-secreting pituitary adenomas.

Glucocorticoid replacement therapy and vertebral fractures in hypopituitary adult males with GH deficiency

OBJECTIVE GH deficiency (GHD) and glucocorticoid excess are associated with increased risk of fragility fractures. We aimed to evaluate whether the prevalence of vertebral fractures may be influenced by glucocorticoid over-replacement in hypopituitary males with GHD. DESIGN Cross-sectional study. METHODS Fifty-one adult hypopituitary patients (all males; mean age 55 years, range: 23-81) with severe adult-onset GHD (replaced in 21 patients and untreated in 30 patients) and glucocorticoid deficiency on replacement treatment were studied for vertebral fractures using a radiological and morphometric approach. RESULTS Vertebral fractures were observed in 31 patients (60.8%) in correlation with untreated GHD, urinary cortisol values, and cortisone doses. Patients were stratified according to treatment of GHD, and current and cumulative cortisone doses. In untreated GHD, vertebral fractures occurred more frequently in patients who had received higher (greater than median) cumulative and current doses of cortisone compared with patients who had received lower (less than median) drug doses (95.2 vs 50.0%, P=0.009 and 90.5 vs 55.6%, P=0.04 respectively). In untreated GHD, fractured patients had significantly higher urinary cortisol values compared with patients without vertebral fractures (84 microg/24 h, range: 24-135 vs 49 microg/24 h, range: 30-96; P=0.04). In treated GHD patients, by contrast, the prevalence of vertebral fractures was not influenced by cumulative and current cortisone doses and urinary cortisol values. CONCLUSIONS Glucocorticoid over-replacement may increase the prevalence of vertebral fractures in patients with untreated GHD. However, treatment of GHD seems to protect the skeleton from the deleterious effects of glucocorticoid overtreatment in hypopituitary patients.

Effect of gonadal status on bone mineral density and radiological spinal deformities in adult patients with growth hormone deficiency

Growth hormone deficiency (GHD) in adult patients is associated with marked decrease in bone turnover, low bone mass and high risk of clinical and subclinical fractures. We investigated whether the prevalence of spinal deformities in adults with GHD was related to the gonadal status of patients. A total of 89 adult hypopituitary patients with severe GHD were evaluated for bone mineral density (BMD) and vertebral deformities (quantitative morphometric analysis). At the study entry, 54 patients were eugonadic whereas 35 patients were hypogonadic without replacement treatment. Radiological spinal deformities were found in 55 patients (61.8%) with higher prevalence in untreated (56 cases) versus treated (33 cases) GHD patients. Eugonadic and hypogonadic patients showed no significant difference in spinal deformities although T-score was significantly lower in hypogonadic as compared with eugonadic patients. Gonadal function was not correlated with the occurrence of spinal deformities which was instead inversely correlated with rhGH treatment. In conclusion, gonadal status may influence BMD in adult patients with GHD without affecting the risk to develop vertebral deformities. Conversely, rhGH replacement treatment seems to be the only factor influencing the risk to develop vertebral deformities in adult GHD patients.

Nonalcoholic fatty liver disease is associated with increased GHBP and reduced GH/IGF-I levels

Introduction  Nonalcoholic fatty liver disease (NAFLD) has been described in adult GH deficiency syndrome. Furthermore, chronic liver disease can be associated with significant changes in levels of IGF‐I, GH‐binding protein (GHBP), IGF‐binding proteins (IGFBPs) and acid‐labile subunit (ALS). However, the effect of liver steatosis on the GHBP production has not been investigated yet.

Effects of ghrelin administration on endocrine and metabolic parameters in obese women with polycystic ovary syndrome

Introduction: The novel peptide ghrelin displays multiple endocrine and non-endocrine actions. Its strong GH-releasing activity in humans has long been recognized. However, in obesity, ghrelin administration induces a blunted GH secretion, enhances glucose and reduces insulin levels. The effects of ghrelin administration have not been investigated in polycystic ovary syndrome (PCOS), which can be associated with obesity, hyperinsulinism, and GH hyposecretion. Leptin is a mediator for energy balance opposed to ghrelin; both of them are supposed to act as regulators of reproductive functions. Aim of the study: Evaluate the endocrine and metabolic response to ghrelin administration in PCOS obese patients compared to body mass index (BMI)-matched and normal weight women. Materials and methods: Nine obese PCOS patients (BMI: 35.4±1.2 kg/m2) (OB PCOS), 6 obese controls (BMI: 38.4±1.1 kg/m2) (Ob), and 6 normal-weight women (BMI: 23±0.6 kg/m2) (NW) were enrolled in the study. In all patients we performed: 1) basal hormonal evaluation including FSH, LH, estradiol, testosterone, androstenedione, DHEAS, SHBG, 17-hydroxyprogesterone (17OHP), IGF-I, free T3 (FT3), free T4 (FT4) and ghrelin levels; 2) metabolic evaluation as follows: concentration of non-esterified fatty acid (NEFA) and oral glucose tolerance test (OGTT) (75 g); homeostasis model assessment (HOMA); glucose and insulin response to ghrelin administration (1 µg/kg); 3) measurement of GH, PRL, TSH, and leptin levels after infusion of ghrelin. Results: Administration of ghrelin increased glucose and reduced insulin levels in both Ob and OB PCOS. Moreover, ghrelin enhanced GH and PRL levels in all groups but it did not modify TSH and leptin levels. GH peak and area under the curve (AUC) in OB PCOS and Ob were lower than controls (p<0.05). Similar PRL peak and AUC values were observed in all groups. Conclusions: In both obese and PCOS obese patients, leptin levels are not influenced by ghrelin administration. Moreover, the GH response after ghrelin administration is blunted. However, ghrelin exerts glucose-enhancing and insulin-lowering effects, the latter absent in NW.

The effect of treatment with growth hormone on fertility outcome in eugonadal women with growth hormone deficiency: report of four cases and review of the literature.

OBJECTIVE To highlight the clinical role of standard GH replacement treatment on fertility and pregnancy outcomes in four infertile eugonadal women with GH deficiency (GHD). DESIGN Case report. SETTING Department of endocrinology and infertility clinic, tertiary-care university hospital. PATIENT(S) Four normogonadotrophic, normoprolactinemic patients with long-standing infertility, affected by GHD. In two patients (aged 30 and 34 years) GHD was diagnosed after a brain injury. The third patient (age 30 years) had a primary empty sella, documented by magnetic resonance imaging of the pituitary. The last patient (age 28 years) underwent transsphenoidal surgery for Ratkes cyst. The LH and FSH responses to GnRH were normal in all four patients. Two of the four patients also had secondary hypoadrenalism and hypothyroidism. INTERVENTION(S) Patients received recombinant human GH replacement therapy (0.9-1.8 mg/week) for 6-12 months until pregnancy was first indicated by biochemical markers (beta-hCG) and later confirmed by transvaginal sonography. The GH therapy was discontinued after confirmation of pregnancy. MAIN OUTCOME MEASURE(S) Pregnancy. RESULT(S) All patients remained off treatment throughout pregnancy; they had uneventful pregnancies and term deliveries. The babies were healthy and normal in terms of length and weight. CONCLUSION(S) Our case studies confirm the important clinical role of the GH-insulin-like growth factor I system in oocyte fertilization and the beginning of pregnancy in a selected population of eugonadotrophic infertile women.